This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California at San Diego in consortium with the Salk Institute. The major objective of our ADRC is to understand the pathogenesis and pathophysiology of AD with the ultimate goal of understanding the etiology sufficiently to be able to prevent it or slow its course. This center is focused on structure- functional relationships, made possibly by the close links between the Clinical and Neuropathology Cores. We will carry out a series of specific clinical pathological correlations complemented by studies of molecular events in AD in order to understand the disease. The ADRC provides an invaluable clinical and neuropathological resource to both ADRC and other AD investigators and to the San Diego community as a whole by making available a well characterized clinical cohort of both Caucasian and Hispanic volunteers who undergo annual evaluations and are willing to participate in clinical research. We also supply brain tissue, fibroblasts, serum, DNA and cerebrospinal fluid to numerous investigators. The Clinical Core also recruits special subjects and controls to support the special needs of many of the individual projects. These cohorts are subjects also participate in both multicenter drug trials and registries such as CERAD. The ADRC provides a setting to facilitate research training of AD investigators and information is transferred to the professional and lay communities through our mini- residency program, conferences and other educational activities. We foster interdisciplinary research activities through collaborations, seminars, feasibility and pilot projects. Our specific research projects in this renewal include research into: The Role of Glutamate Receptor Activation in AD; Beta Amyloid Protein Metabolism in vitro; A novel Amyloid Component; Synaptic Alterations in Rodent Models of AD; Early Brain Structural Changes in Subjects at Risk for proposed including: Human Fetal Neuronal Cultures for AD; Bilingualism and Dementia; Quantitative MRI Analysis of Psychosis in AD; the Deterioration of Semantic Networks in Patients with AD; and the Biological Activity of the Secreted Form of APP-751.